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PubMed1987

Role of sodium and potassium permeabilities in the depolarization of denervated rat muscle fibres.

1. Na+ and K+ flux measurements and membrane potential (Vm) determinations were performed on normal and denervated rat extensor digitorum longus (e.d.l.) muscles. 2. The mean Vm in normal muscle fibres was -74.6 mV. During the first week after denervation Vm fell about 20 mV following an S-shaped time course. 3. In that period the Na+ permeability (PNa) increased and the K+ permeability (PK) decreased, so that by the sixth day post-denervation, the PNa/PK ratio was increased by a factor of 2.7. 4. The decrease in PK preceded the increase in PNa. 5. No major contribution to the fall of Vm by a reduced activity of an electrogenic Na+ pump could be detected. 6. A good agreement was found between the experimental values of the depolarization and those calculated using the constant-field equation assuming Cl- is at equilibrium and no significant change of the intracellular K+ concentration ([K+]i) during the first week after denervation. 7. It is concluded that the depolarization promoted by denervation in e.d.l. rat muscle fibres can be fully explained in terms of changes in PNa and PK.

Animals↗
PubMed1975

Loss of alpha-bungarotoxin from junctional and extrajunctional acetylcholine receptors in rat diaphragm muscle in vivo and in organ culture.

Acetylcholine (ACh) receptors in rat diaphragm muscle were blocked by intrathoracic injection of alpha-bungarotoxin (alpha-BuTx) or [125I]alpha-bungarotoxin ([125I]alpha-BuTx). The stability in vivo of the toxin-receptor complex formed by receptors in normal muscles and receptors in extrajunctional regions of denervated muscles was compared. Toxin was lost from junctional regions of normal muscles with a half-time of approximately 6 days. The loss of toxin was accompanied by a corresponding increase in the number of free toxin-binding sites. In contrast, 65% of the toxin bound to extrajunctional regions of denervated muscle was lost in 24 hr. 2. In a second series of experiments, animals were injected with [125I]alpha-BuTx and the muscle subsequently cultured for 24 hr. Loss of toxin again occurred more rapidly from extrajunctional receptors than from junctional receptors. The loss from extrajunctional receptors was described by a single first-order rate constant whose corresponding half-time was 8-11 hr. Loss was almost completely blocked by sodium cyanide and dinitrophenol and was inhibited by puromycin and cycloheximide. The radioactivity recovered in the medium was largely monoiodotyrosine. These results are consistent with the hypothesis that toxin loss reflects intracellular degradation of toxin-receptor complex. 3. Neonatal rats were injected with [125I]alpha-BuTx and the diaphragms cultured. Radioactive toxin was lost rapidly from extrajunctional regions of muscle and more slowly from regions containing end-plates. 4. These results could be explained by a difference in turnover rates for junctional and extrajunctional receptors.

Animals↗
PubMed1994

AML1 is expressed in skeletal muscle and is regulated by innervation.

Although most skeletal muscle genes are expressed at similar levels in electrically active, innervated muscle and in electrically inactive, denervated muscle, a small number of genes, including those encoding the acetylcholine receptor, N-CAM, and myogenin, are expressed at significantly higher levels in denervated than in innervated muscle. The mechanisms that mediate electrical activity-dependent gene regulation are not understood, but these mechanisms are likely to be responsible, at least in part, for the changes in muscle structure and function that accompany a decrease in myofiber electrical activity. To understand how muscle activity regulates muscle structure and function, we used a subtractive-hybridization and cloning strategy to identify and isolate genes that are expressed preferentially in innervated or denervated muscle. One of the genes which we found to be regulated by electrical activity is the recently discovered acute myeloid leukemia 1 (AML1) gene. Disruption and translocation of the human AML1 gene are responsible for a form of acute myeloid leukemia. AML1 is a DNA-binding protein, but its normal function is not known and its expression and regulation in skeletal muscle were not previously appreciated. Because of its potential role as a transcriptional mediator of electrical activity, we characterized expression of the AML1 gene in innervated, denervated, and developing skeletal muscle. We show that AML1 is expressed at low levels in innervated skeletal muscle and at 50- to 100-fold-higher levels in denervated muscle. Four AML1 transcripts are expressed in denervated muscle, and the abundance of each transcript increases after denervation. We transfected C2 muscle cells with an expression vector encoding AML1, tagged with an epitope from hemagglutinin, and we show that AML1 is a nuclear protein in muscle. AML1 dimerizes with core-binding factor beta (CBF beta), and we show that CGF beta is expressed at high levels in both innervated and denervated skeletal muscle. PEBP2 alpha, which is structurally related to AML1 and which also dimerizes with CBF beta, is expressed at low levels in skeletal muscle and is up-regulated only weakly by denervation. These results are consistent with the idea that AML1 may have a role in regulating gene expression in skeletal muscle.

Animals↗
PubMed1992

Contractility of mdx skeletal muscle after denervation and devascularization.

To evaluate the regenerative capacity of mdx skeletal muscle, changes in contractile properties of the fast-twitch extensor digitorum longus (EDL) of normal and mdx mice were studied at 7 and 16 weeks of age, following denervation and devascularization (DD) at 4 weeks of age. At 7 weeks, DD EDL of both strains showed significantly decreased isometric twitch and tetanus tensions compared with their non-DD controls. By 16 weeks, normal operated muscle exhibited a recovery of 57% and 58% of absolute tetanus and twitch tensions while the mdx EDL recovered remarkably to 96% and 99% of 7-week values. At 7 weeks, the DD EDL of both strains exhibited significantly slower time-to-peak (TTP) and one-half relaxation time (1/2RT). By 16 weeks, TTP and 1/2RT of the mdx DD EDL no longer differed from non-DD controls, but the normal EDL showed slowed TTP. No differences were found in the maximum velocity of shortening (Vo) or in posttetanic potentiation (PTP). Following DD, there was an increase in resistance to fatigue in both strains at 7 weeks. This resistance persisted at 16 weeks in the normal mouse, but the operated mdx EDL returned to normal. It would appear that following a denervation/devascularization insult, the mdx EDL is able to recover contractile characteristics to a remarkably larger extent than normal EDL.

Animals↗
PubMed1985

ConA and WGA receptors in rat skeletal muscles. Changes in density, distribution and composition following denervation.

The differential binding of fluorescein-labeled ConA, WGA and UEA to cryostatic sections of control and of 8 days denervated muscles is described. Receptor sites for ConA and WGA appear to be very abundant in skeletal muscles and their abundance seems to increase following denervation. In contrast, concentration of receptor sites for UEA is below the sensitivity of the method. Differences in the distribution of the binding sites for ConA and WGA, apparent in untreated sections, were further analysed following predigestions by collagenase, hyaluronidase or neuraminidase. The most important difference among lectins appeared to be the preferential binding of ConA to the surface of muscle fibres and of WGA to connective tissue. By comparing results in control and denervated muscles a clear change of the effects of neuraminidase on WGA binding was evident following denervation. The binding of fluorescein-labeled ConA and WGA to untreated and to predigested cryostatic sections of skeletal muscle is a sensitive and simple histochemical method which can disclose precocious changes in composition of glycoconjugates following denervation and, what might be useful, in other experimental or pathological conditions.

Animals↗
PubMed1993

Morphological correlates of physiological responses in partially denervated mouse muscle during aging.

To evaluate the effect of partial denervation on age changes, morphological and physiological parameters were studied in young versus old extensor digitorum longus (EDL) muscles. The aims of this study were to elucidate synaptic maintenance in general and specifically to assess the adaptability of motor neurons from young and old animals to an enlarged field of innervation. Partial denervation was carried out in two groups of 30-40 g mice, aged within 6 or 24 months, by sectioning of the nerve supplying EDL muscle under methoxyfluorane anaesthesia. Sham operations were carried out on additional animals which served as controls. Five weeks' post-surgery, the safety factor of synaptic transmission was estimated by dividing the nerve-evoked twitch tension generated in 1 mM Ca2+ Krebs by that generated in 2.5 mM Ca2+ Krebs. Low Ca2+ Krebs caused a more pronounced decline in twitch tension in young control EDL muscles than old control. After partial denervation, young EDL twitch tensions were not significantly different while old were 20% of those in normal Krebs. Zinc Iodide Osmium (ZIO) stained nerve terminal parameters were significantly increased with aging. After partial denervation, nerve terminal areas were 46 and 39% larger in young and old mice, respectively, compared to their corresponding controls. Present data suggest that motor neurons of old mice are unable to develop and maintain an enlarged field of innervation.

Aging↗
PubMed1984

Morphology of denervated human facial muscles.

17 biopsies of denervated facial muscles, the zygomatic, the orbicularis oris and the levator labii muscles, showed atrophic myofibers in most cases. There was loss of fiber typability when applying the NADH, the MAG and the alkaline ATPase reactions. The acid ATPase preparations allowed differentiation of myofibers into type I and type II without subtypes. Contrary to normal facial muscles that are richly endowed with motor endplates, no neuromuscular junctions were observed in denervated muscle fibers except one example which might have been obtained by false sampling from the marginal area of denervation or might be the result of partial reinnervation due to sprouting axons from the neighborhood. There was no correlation between the degree of muscle fiber atrophy and the duration of the paralysis. However, fibrosis corresponded to length of denervation. The presence of highly atrophic muscle fibers even 36 years after denervation indicates that the final aim of facial nerve surgery, namely the reinnervation of denervated facial musculature may still be achievable. However, endomysial and perimysial fibrosis may have a considerable impact on the final outcome of such facial nerve surgery. Unsatisfactory correlation between morphological and clinical as well as electromyographical findings in denervated facial muscles requires individual morphological study of each biopsy to assess the probable outcome of reconstructive facial nerve surgery. It therefore appears reasonable even in long-standing facial paralysis, to biopsy denervated facial muscles before or during surgical reanastomosation of the facial nerve. This study provides hints that morphological examination of denervated facial muscles may supplement clinical, electrophysiological, and possibly biochemical diagnostic findings.

Adolescent↗
PubMed1990

Neurite outgrowth and proliferation of non-neuronal cells on cryostat sections of adult muscle.

Rat spinal cord cells were cultured on cryostat sections of innervated and denervated muscle. Neurite outgrowth was greater on sections of denervated muscle, which therefore appeared to act on in vivo nerve regeneration. It seems that muscle sections were able to release into the culture medium factors that increase proliferation of fibroblasts. The muscle therefore appeared able to modulate its interaction with its environment by acting on different types of cells.

Animals↗
PubMed1995

Response to denervation of rabbit soleus and gastrocnemius muscles. Time-course study of postnatal changes in myosin isoforms, fiber types, and contractile properties.

In contrast to general belief, the response of rabbit muscles to denervation is maturation to slow-like type muscles [7]. We report now an investigation by biochemical, morphological, and mechanical studies of the time course effects of muscle denervation on the slow-type soleus and fast-type gastrocnemius to help elucidate the mechanism of maturation of rabbit denervated muscles to slow-like muscles. In both muscles, denervation induced selective progressive atrophy of most fast fibers and hypertrophy of many slow fibers which displayed wide Z-lines; this was accompanied by the appearance of hybrid LC1F- and LC1E-associated slow myosins. The percentage of slow myosins increased with age similarly in the contralateral and denervated soleus. On the other hand, the percentage of slow myosins remained low in the contralateral gastrocnemius, whereas it increased to 95% in the denervated gastrocnemius; in the denervated gastrocnemius, the percentage of slow myosins reached 50% at about 35 days postnatal. At this age, the maximal shortening velocity of the denervated gastrocnemius and its twitch contraction time were already those of a slow-type muscle. This suggests that in addition to myosin, other proteins contributed to the mechanical properties of the denervated gastrocnemius. Transformation of rabbit denervated muscles to slow-like type muscles, which are associated with a lower energy requirement and higher muscle endurance than fast-type muscles, may constitute an adequate model for human neuromuscular pathology.

Aging↗
PubMed1982

Differentiation of spontaneous activity from normal and denervated skeletal muscle.

The discrimination of fibrillation potentials and endplate potentials based on the conventional EMG methods is difficult if there is only discrete denervation. The reliability of discrimination can be highly improved if the frequency behaviour of the potentials is taken into account. The average proportional consecutive interval difference is the best discrimination variable with 90% correct findings per analysed potential sequence. When three analyses per muscle are made, the accuracy increases to 97.2%. The second best variable is the mean consecutive difference followed by interval bandwidth, standard deviation of interval, minimum interval and finally maximum interval. The mean duration of intervals does not allow of any differentiation. The frequency analysis can be restricted to spontaneous activity sequences of ten seconds. It is immaterial which part of a prolonged sequence is analysed for ten seconds. The conventional evaluation of registered spontaneous activity either alone or with observation at the monitor under simultaneous acoustic control is inferior to the frequency analysis. The results do not allow a statement of the probability of wrong diagnosis in clinical routine work.

Action Potentials↗
PubMed1994

The use of embryonic spinal cord grafts to replace identified motoneuron pools depleted by a neurotoxic lectin, volkensin.

The viability of solid pieces of embryonic spinal cord grafted into adult spinal cords that had been depleted of motoneurons by a neurotoxic lectin, volkensin, was investigated. The possibility that the grafted neurons will extend their axons via the degenerated ventral roots and reinnervate the denervated muscles was also studied. Cells in the embryonic spinal cord were prelabeled with bromodeoxyuridine and grafted into the host cord 2 or 3 weeks after volkensin treatment. Six to 24 weeks later the fluorescent dyes Fast Blue and Diamidino Yellow were applied to the peripheral nerve or muscles which were expected to be reinnervated by neurons from the graft. The grafted cells were visualized by bromodeoxyuridine immunocytochemistry. Although the transplants survived, no neurons of graft origin reinnervated the muscles via the ventral roots of the host spinal cord. Therefore, in another series of experiments axons from grafted and host neurons were guided toward an implanted extensor hallucis longus (EHL) muscle via its motor nerve. The EHL muscle was removed from either healthy or volkensin-affected hindlimb of the host, placed paravertebrally, and the proximal end of its motor nerve inserted into the spinal cord at the site of the graft. In these experiments, neurons of graft origin reinnervated the paravertebrally placed muscle implant via the muscle's own nerve. However, significantly fewer neurons were observed when volkensin-affected nerve-muscle implants were used. To establish whether grafted spinal cord neurons are necessary for reinnervation of skeletal muscles, in separate experiments embryonic neocortical tissue was transplanted into the motoneuron-depleted spinal cord. These grafts were connected to healthy nerve-muscle implants. In this case little reinnervation of the muscle occurred. These results suggest that, though volkensin-affected peripheral nerve is not a good conduit for regenerating axons, other inhibitory effects located in the CNS may be responsible for the failure of growing embryonic neurons to reach their peripheral targets via the existing anatomical routes. Experiments with grafted neocortical tissue indicate that good reinnervation of implanted muscles can only be achieved by using homologous embryonic tissue.

Acetylcholinesterase↗
PubMed1994

Repetitive discharge due to self-ephaptic excitation of a motor unit.

Repetitive discharges (RDs) of a motor unit action potential were evoked by nerve stimulation in chronically denervated muscles of 3 patients. One RD also occurred at rest and during voluntary contraction. The 3 RDs had a regular firing frequency of respectively 16, 27 and 28.5 c/sec. Double stimulation evoked an RD consisting of doublets. An ectopic discharge arising during the RD had the same effect. These observations make likely that such RDs result from a 1-way ephaptic reverberating excitation occurring within a single MU. The synchronized potential of muscle fibres grouped by reinnervation may re-excite an axonal branch of the same MU, thus initiating a reverberating loop.

Action Potentials↗
PubMed2002

Impact of innervation and exercise on muscle regeneration in neovascularized muscle grafts in rats.

The direction of known staged process of regeneration of free muscle grafts was inverted in our experimental rat model from a centripetal to a centrifugal by central implantation of blood vessels into isolated free muscle grafts. The effects of innervation, reinnervation and exercise on muscle fiber regeneration were analyzed at various intervals from 4 to 90 days by morphological and morphometric methods. Reinnervation occurred as well in grafts with the motor nerve left intact as it did in grafts with a severed and reimplanted nerve. Reinnervation proved to be prerequisite for a lasting muscle regeneration. Denervated muscle grafts even after neovascularization underwent irreversible fibrosis. A positive effect of exercise on the early states (30 days) of muscle regeneration was revealed by morphometrical analysis. In the long term (90 days) fiber diameter assimilated in all groups. The animal model mimics a clinical situation of flap prefabrication demonstrating the relationship of functional tissue regeneration and neovascularization. It can be transferred into the acute clinical situation as well as in tissue engineering.

Animals↗
PubMed2001

Basic design and construction of the Vienna FES implants: existing solutions and prospects for new generations of implants.

We can distinguish 3 generations of FES implants for activation of neural structures: 1. RF-powered implants with antenna displacement dependent stimulation amplitude; 2. RF-powered implants with stabilised stimulation amplitude; and 3. battery powered implants. In Vienna an 8-channel version of the second generation type has been applied clinically to mobilisation of paraplegics and phrenic pacing. A 20-channel implant of the second generation type for mobilisation of paraplegics and an 8-channel implant of the third generation type for cardiac assist have been tested in animal studies. A device of completely new design for direct stimulation of denervated muscles is being tested in animal studies. There is a limited choice of technologically suitable biocompatible and bioresistant materials for implants. The physical design has to be anatomically shaped without corners or edges. Electrical conductors carrying direct current (D.C.) have to be placed inside a hermetic metal case. The established sealing materials, silicone rubber and epoxy resin, do not provide hermeticity and should only embed DC-free components. For electrical connections outside the hermetic metal case welding is preferable to soldering; conductive adhesives should be avoided. It is advisable to use a hydrophobic oxide ceramic core for telemetry antenna coils embedded in sealing polymer. Cleaning of all components before sealing in resin is of the utmost importance as well as avoidance of rapid temperature changes during the curing process.

Animals↗
PubMed1980

Beta-adrenergic dilator interaction with the constrictor response in resistance vessels of skeletal muscle during hemorrhage.

A marked beta-adrenergic dilator interaction with the vasoconstrictor response in skeletal muscle during hemorrhage is described. The dilator influence corresponded to some 40% of the constrictor response both at mild and moderate as well as at large bleeding. In absolute resistance units, the beta-adrenergic dilator influence averaged no less than 14 mmHg/ml X min-1 X 100 g-1) at large bleeding (hemorrhagic hypotension of 50 mmHg). Comparison of the hemorrhage induced resistance effects in the autoperfused innervated muscle, in the autoperfused denervated muscle, and in the innervated muscle cross-circulated from a donor animal, showed that the beta-adrenergic dilator influence more or less completely was caused by blood-borne catecholamines, in all likelihood by adrenaline, which is known to be secreted in large amounts during hemorrhage. The described beta-adrenergic dilator mechanism may serve to maintain nutritional blood flow by counteracting the constrictor response. It deserves consideration also from the point of view that it obviously has to be taken into account for proper evaluation of other vascular control mechanisms brought into action in hemorrhage.

Animals↗
PubMed1989

Expression of diverse Na+ channel messenger RNAs in rat myocardium. Evidence for a cardiac-specific Na+ channel.

This study examined the diversity of Na+ channel gene expression in intact cardiac tissue and purified myocardial cells. The screening of neonatal rat myocardial cell cDNA libraries with a conserved rat brain Na+ channel cDNA probe, resulted in the isolation and characterization of a putative rat cardiac Na+ channel cDNA probe (pCSC-1). The deduced amino acid sequence of pCSC-1 displayed a striking degree of homology with the eel, rat brain-1, and rat brain-2 Na+ channel, thereby identifying pCSC-1 as a related member of the family of Na+ channel genes. Northern blot analysis revealed the expression of a 7-kb CSC-1 transcript in rat cardiac tissue and purified myocardial cells, but little or no detectable expression of CSC-1 in rat brain, skeletal muscle, denervated skeletal muscle, or liver. Using RNase protection and Northern blot hybridization with specific rat brain Na+ channel gene probes, expression of the rat brain-1 Na+ channel was observed in rat myocardium, but no detectable expression of the rat brain-2 gene was found. This study provides evidence for the expression of diverse Na+ channel mRNAs in rat myocardium and presents the initial characterization of a new, related member of the family of Na+ channel genes, which appears to be expressed in a cardiac-specific manner.

Amino Acid Sequence↗
PubMed2005

Impaired regeneration of bcl-2-lacking peripheral nerves.

OBJECT: The outcome of peripheral nerve damage in still not satisfactory, despite the general capacity of peripheral nervous system to regenerate. The molecular mechanisms underlying nerve regeneration are still not clear, but it is likely that apoptosis regulating genes plays a crucial role in these processes. The aim of the present study was to establish the role of the anti-apoptotic gene bcl-2 in peripheral nerve repair. MATERIAL AND METHODS: Sciatic nerves of bcl-2-deficient and wild type mice were transected, and immediately re-sutured. The regeneration was assessed functionally and morphologically throughout the 4-week follow-up. RESULTS: We found markedly worse sciatic function index outcome, as well as more significant atrophy of denervated muscles in bcl-2 knock-out animals when compared with wild-type ones. The intensity of histological regeneration features, including GAP-43-positive growth cones, Schwann cells and macrophages in the distal stump of the transected nerve, was also decreased. The number of motor and sensory neurons in the relevant cross-sections of spinal cord was similar in both groups of mice. CONCLUSION: We concluded that the bcl-2 gene plays an important role in peripheral nerve regeneration, influencing nerve injury site clearing, fiber regrowth and myelination.

Animals↗